Design, synthesis and biological evaluation of paralleled Aza resveratrol-chalcone compounds as potential anti-inflammatory agents for the treatment of acute lung injury

Article abstract of DOI:10.1016/j.bmcl.2015.05.030

Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. It has been reported that both resveratrol and chalcone derivatives could ameliorate lung injury induced by inflammation. A series of paralleled Aza resveratrol-chalcone compounds (5a-5m, 6a-6i) were designed, synthesized and screened for anti-inflammatory activity. A majority showed potent inhibition on the IL-6 and TNF-α expression-stimulated by LPS in macrophages, of which compound 6b is the most potent analog by inhibition of LPS-induced IL-6 release in a dose-dependent manner. Moreover, 6b exhibited protection against LPS-induced acute lung injury in vivo. These results offer further insight into the use of Aza resveratrol-chalcone compounds for the treatment of inflammatory diseases, and the use of compound 6b as a lead compound for the development of anti-ALI agents.

Full text of DOI:10.1016/j.bmcl.2015.05.030

Accepted Manuscript
Design, synthesis and biological evaluation of paralleled Aza resveratrol-chal-
cone compounds as potential anti-inflammatory agents for the treatment of acute
lung injury
Wenbo Chen, Xiangting Ge, Fengli Xu, Yali Zhang, Zhiguo Liu, Jialing Pan,
Jiao Song, Yuanrong Dai, Jianmin Zhou, Jianpeng Feng, Guang Liang
PII:
S0960-894X(15)00480-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.030
BMCL 22720
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 February 2015
8 May 2015
12 May 2015
Please cite this article as: Chen, W., Ge, X., Xu, F., Zhang, Y., Liu, Z., Pan, J., Song, J., Dai, Y., Zhou, J., Feng, J.,
Liang, G., Design, synthesis and biological evaluation of paralleled Aza resveratrol-chalcone compounds as potential
anti-inflammatory agents for the treatment of acute lung injury, Bioorganic & Medicinal Chemistry Letters (2015),
doi: http://dx.doi.org/10.1016/j.bmcl.2015.05.030
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Design, synthesis and biological evaluation of paralleled Aza resvera-
trol-chalcone compounds as potential anti-inflammatory agents for the
treatment of acute lung injury
Wenbo Chen a, #, Xiangting Ge b, #, Fengli Xu b, Yali Zhang a, Zhiguo Liu a, Jialing Pan a, Jiao Song a, Yuanrong Dai b,
Jianmin Zhou c, *, Jianpeng Feng a, *, Guang Liang a
a Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 Uni-
versity Town, Wenzhou, Zhejiang 325035, China
b
Department of respiration, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang
325027, China.
c
School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang
325035, China
Jianmin Zhou, Professor
School of Pharmaceutical Sciences, Wenzhou Medical University. 1210 University Town, Wenzhou, Zhejiang 325035,
China
Tel: (+86)-577-86689819; Fax: (+86)-577-86689819
E-mail: zjm@wzmc.edu.cn
Jianpeng Feng, Ph.D, Associate Professor
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University. 1210 Univer-
sity Town, Wenzhou, Zhejiang 325035, China
Tel: (+86)-577-86699892; Fax: (+86)-577-86699892
E-mail: chemime@163.com
Abstract
Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. It has
been reported that both resveratrol and chalcone derivatives could ameliorate lung injury induced by
inflammation. A series of paralleled Aza resveratrol-chalcone compounds (5a-5m, 6a-6i) were de-
signed, synthesized and screened for anti-inflammatory activity. A majority showed potent inhibition
on the IL-6 and TNF-α expression-stimulated by LPS in macrophages, of which compound 6b is the
most potent analog by inhibition of LPS-induced IL-6 release in a dose-dependent manner. Moreover,
6b exhibited protection against LPS-induced acute lung injury in vivo. These results offer further in-
sight into the use of Aza resveratrol-chalcone compounds for the treatment of inflammatory diseases,
and the use of compound 6b as a lead compound for the development of anti-ALI agents.
Keywords: Aza resveratrol, Chalcone, parallel, anti-inflammatory, acute lung injury.
1

Inflammation is a hallmark of many diseases and the persistence of this process may lead to various diseases
associated with acute or chronic inflammation, including acute lung injury, sepsis,1 arthritis, diabetic nephropa-
thy,2 atherosclerosis, and even cancer.3 Specifically, acute lung injury (ALI) is a major cause of acute respira-
tory failure in critically-ill patients. Pro- and anti-inflammatory cytokines, including Interleukin(IL)-1, IL-6
and TNF-α, have been reported to play a major role in the pathogenesis of inflammatory-induced lung injury
from sepsis, pneumonia, aspiration, and shock.4 IL-6 is an important pro-inflammatory cytokines that is in-
volved in the induction of fever, inflammation,5 diabetic complications,6 atherosclerosis and cancer.7 A number
of pro-inflammatory cytokines have been successful inhibited in preclinical and clinical studies for the treat-
ment of sepsis, cancer and rheumatoid arthritis. However, due to drug resistance and harmful side effects, clin-
ical application has been limited in conventional treatment methods. As such, there is an urgent need for the
development of new anti-inflammatory drugs.8
Resveratrol is a natural polyphenol stilbene found in grapes and certain plants used medicinally. Resveratrol
has been reported to have a diverse range of beneficial effects on several important pathologies both in vitro
and in vivo, such as in vascular diseases, cancers, viral infections and inflammation.9 Because of the relatively
high concentration of resveratrol in red wine, it has even been advocated by some as the agent responsible for
the “French Paradox”. However, the rapid metabolism of resveratrol’s three hydroxyl groups leads to the pro-
duction of sulfates and glucuronides in vivo (initial half-life of resveratrol is only 8-14 min), therefore, despite
its efficient absorption after oral administration, resveratrol has low bioavailability. Many resveratrol analogs
have been designed and synthesized to improve its pharmacological activities or pharmacokinetics. Among
these analogs, Aza resveratrol, which replaces one carbon atom of the conjugated double by one nitrogen atom,
has shown good performance. Moreover, many clinical anti-inflammatory drugs have been found to contain
nitrogen atoms,10 such as indomethacin and celecoxib, which belong to a class non-steroidal anti-inflammatory
drugs. Furthermore, chalcones were reported to have many useful medical applications, including anti-
inflammatory, antimicrobial, antifungal, antioxidant, cytotoxic, antitumor and anticancer activities. A struc-
ture-activity relationship (SAR) examination of chalcone analogs activity demonstrated that the presence of an
α, β-unsaturated ketone structure is critical for their activities.11
Currently, an effective and widely-used strategy is the design and development of new bioactive agents
based on a molecular paralleling strategy or the integration of two or more pharmacophoric units with different
mechanisms of action in the same molecule.12 In combination with Ratchanok Pingaew et al.’s paralleling
strategy with a series of chalcone-coumarin hybrids (anticancer and antimalarial agents),13 we also integrated
the skeleton of resveratrol and chalcone into the same molecule to enhance anti-inflammatory activity and in-
duce cytotoxicity. Herein, several Aza resveratrol-chalcone derivatives were designed and synthesized as
shown in Figure 1. Through the optimization of R1 R2 and the screen of anti-inflammatory activities, we found
,
that compound 6b had potent anti-inflammatory activity and may be a potential candidate drug for treating
ALI.
2

Please insert Figure 1
Structural optimization focused on the R1 and R2 groups in the new scaffold where we expected to find po-
tential compounds with excellent anti-inflammatory activities through R1 and R2 group alterations. Previously,
our group found that mono-carbonyl analogs of curcumin containing either 2-hydroxy14 or 3-methoxy15 groups,
showed potent anti-inflammatory activity. We proposed that having both 2-hydroxy and 3-methoxy groups in a
compound may have an important role in bioactivity. Thus, we selected initially 2-hydroxy-3-methoxylphenyl
as R2, and synthesized thirteen Aza resveratrol-chalcone analogs, 5a-5m, by varying the R1 groups, which
came from chalcone derivatives with good anti-inflammatory activities,16 the structure shown in Table 1.
Through a screening of in vitro bioactivities, we chose the most active compound 5h as a lead compound for
further optimization, while keeping R1 constant, and then nine Aza resveratrol-chalcone derivatives, 6a-6i,
were synthesized by changing the substituents of R1, the structure shown in Table 2.
Please insert Table 1
Please insert Table 2
To make compounds 5a-5m and 6a-6i, commercial available 1-(4-methoxyphenyl)ethan-1-one (1) was cho-
sen as the starting material. The 3-position nitration product 2 was obtained in the presence of concentrated
nitric acid because of the inductive effect of the 4-position methoxyl group. The nitro group in product 2 was
then reduced by hydrogen in the presence of 10% Pd/C and generated aniline derivative 3. Compounds 4a-4m
were obtained from compound 3 via aldol condensation with different aromatic aldehydes in the presence of
20% NaOH. Compounds 5a-5m were obtained from 4a-4m with 2-hydroxy-3-methoxybenzaldehyde, respec-
tively, as shown in Scheme 1. The synthetic preparations for compounds 6a–6i were similar to the synthesis of
5a-5m, and they were obtained through the condensation compound 4h with various aromatic aldehydes, as
shown in Scheme 2. All the new products were isolated by conventional work-up. Analytical and spectral data
of all synthesized compounds were in full agreement with the proposed structures.
Please insert Scheme 1
Please insert Scheme 2
Lipopolysaccharides (LPS) are structural components of the outer membranes of Gram-negative bacteria
and are also potent inducers of inflammatory cytokines in mammals. In this study, we used LPS to simulate an
inflammatory environment as the testing model.17 Target compounds (5a-5m, 6a-6i) were evaluated for their
anti-inflammatory activity by inhibiting IL-6 and TNF-α release in LPS-stimulated mouse macrophage cell
line RAW 264.7 cells.
The ability of the tested compounds to reduce pro-inflammatory cytokines IL-6 and TNF-α is depicted in
Figure 2. It is evident that the substituents in the R1 and R2 effect the anti-inflammatory activity of the mole-
3

cules on RAW 264.7 cells significantly. The anti-inflammatory data also showed that 3,4,5-trimethoxyphenyl
at R1 (5h) exhibited the best results among the structure analogs 5a-5m. We also found that the introduction of
electron-withdrawing groups in the aromatic ring of R1, such as 5a, 5c, 5g, 5i and 5l, substituted in the meta
position of aromatic ring to have a better inhibitory activity than ortho or para substitution. With respect to
electron-donating substitution analogs, the four containing-methoxyl substituent derivatives of 5b, 5m, 5j and
5h all showed relatively good inhibitory activity. In addition, the test results suggested that the quantity and
position of substituents have a significant impact on anti-inflammatory activity, although both of 5h and 5j has
three methoxyl substituent groups. Although with the same amount methoxyl substituent, 5h exhibited approx-
imately a 2-fold higher inhibition than 5j against LPS induced IL-6 expression. Moreover, 5h also showed bet-
ter inhibitory abilities than 5m and 5b, which suggested that 3,4,5-trimethoxyphenyl at the R1 position should
be subjected to further research as it had potent anti-inflammatory effects.
After optimization of the R1 position with 3,4,5-trimethoxyphenyl, we then focused efforts on varying the R2
position using different substituents. In order to understand the significance and role of the substituted groups
in the R2, with respect to the bioactivity properties of the analogs, we replaced the 2-hydroxy-3-methoxyphenyl
group in 5h with a variety of aldehydes available in our lab, as shown in Scheme 2. The anti-inflammatory
bioactivities shown in Figure 2 (A, B), indicated that most of the compounds exhibited good inhibitory activi-
ties against IL-6 and TNF-α. Additionally, 6b exhibited similar anti-inflammatory activity as 5h, with better
bioactivity than others. These results suggested that a 2-hydroxyl substitution in R2 greatly affects anti-
inflammatory efficacy. The rigid structure of benzo[d][1,3]dioxole in 6f limited the conformational flexibility,
causing compound 6f to have an adverse effect related to efficacy. In summary, SAR analysis showed that 6b
is the best candidate in this set of serial analogs. Therefore, we selected this compound for further biological
studies in vitro and in vivo.
Please insert Fig 2
The bioactivity-screening of all compounds indicated that five compounds, 5h, 6b, 6c, 6d and 6e, exhibited
good anti-inflammatory activity. In order to further confirm whether the efficacy of these compounds was due
to the compounds themselves, rather than cytotoxicity, we exposed the compounds to human normal cell line
and examined the results. Firstly, these promising compounds were selected for further assessment of their
cytotoxicity and safety, by MTT after 24 h treatment of the cells with compounds at a concentration of 10 µM.
This is shown in Fig 3A. Of great interest, all of these compounds displayed no obvious toxicity in normal he-
patic cells, indicating that they are relatively safe. It was then necessary to further evaluate their dose-
dependent inhibitory effects against LPS-induced IL-6 release. RAW 264.7 macrophages were pretreated with
6b at indicated concentrations (1, 2.5, 5, 10 µM) for 30 min and were subsequently incubated with LPS (0.5
µg/mL) for 24 h. The release of IL-6 into the culture medium was determined by ELISA. Fortunately, all
showed good dose-dependent response by inhibiting IL-6 expression (Fig 3B). Furthermore, 6b gave indica-
4

tions as being the most promising in activity for inhibition of IL-6 expression in a dose-dependent manner
(IC50=1.8 µM). This results suggest that 6b may be a potential candidate compound for development as an an-
ti-inflammatory agent. Therefore, 6b was selected for further testing against of cytokine-mediated acute lung
injury.
Please insert Figure 3
The possible mechanism underlying the protective effect of 6b needed to be investigated and understood in
more depth. As such, we selected 6b for further study on LPS-induced ALI mice. The concentration of lung
Wet/Dry ratio, inflammatory cell count and total protein were determined to evaluate whether 6b was able to
relieve lung injury in the BALF of ALI mice. As shown in Fig 4A-C, the concentration of lung W/D ratio, total
cell count and total protein were drastically increased after LPS stimulation compared with the control group.
However, pretreatment with 6b (20 mg/kg) for a week effectively reduced the concentration of lung W/D ratio
and total protein and levels, as shown in Figure 4A and 4C respectively, especially total cell count (Figure 4B).
To evaluate the role of 6b in the histopathology changes of lung in LPS-induced ALI mice, we obtained lung
tissues from ALI mice after tracheal instillation by LPS (5 mg/kg) and treatment with or without 6b for 6 hours,
and then used these samples for histological assessment. As depicted in Fig 4D, the LPS group showed notable
pathologic changes, such as inflammatory cell infiltration, interstitial edema, interalveolar septal thickening
compared with the control, which presented a normal structure with no histopathologic changes under light
microscope. Additionally, administration of 6b effectively reduced the airspace inflammation at a concentra-
tion of 10 µM. Overall, these results showed that 6b has a good protective effect on LPS-induced ALI mice.
Please insert Figure 4
Pro-inflammatory cytokines, which occur in the early phase of an inflammatory response, play a critical role
in ALI, and TNF-α is one of the crucial cytokines in ALI. In this study, to investigate the efficacy of 6b on
cytokine production, we selected the levels of TNF-α of BALF and serum from ALI mice as indicators. As
shown in Figure 5(A, B), inflammatory cytokine levels were increased distinctly in BALF and serum after LPS
challenge compared with the control group. However, administration of 6b significantly down-regulated the
levels of TNF-α in BALF of LPS induced ALI mice. Accordingly, these results indicated that the inhibition of
inflammatory cytokines might have contributed to the protective effects of 6b on LPS-induced pulmonary in-
flammation. To confirm these findings, immunohistochemistry analysis of CD68, a macrophage marker, was
performed and depicted in Fig 5C. Increased amounts of CD68-immunostained positive macrophage were ob-
served in the lung sections, whereas there was no significant difference in the number of CD68-stained macro-
phages between 6b and resveratrol pretreatment and control groups. It showed that administration of 6b have a
significant contribution to the therapeutic effect on LPS-induced pulmonary inflammation.
Please insert Figure 5
5

Finally, we evaluated the potency of 6b on the inhibition of inflammatory gene expression at the mRNA
level, with the view of further confirming the anti-inflammatory effects of compound 6b. Beas-2B cells were
treated with LPS (1.0 µg/mL) for 6 h and examined for the expression of pro-inflammatory genes in the pres-
ence or absence of 6b by RT-qPCR. As shown in Figure 6A-D, LPS up-regulated the mRNA expression of
pro-inflammatory cytokines, including IL-1β (A), IL-6 (B), IL-33 (C) and TNF-α (D), while 6b markedly sup-
pressed the mRNA expression of pro-inflammatory cytokines (P<0.01). The data indicates that 6b is a potent
inhibitor of LPS-induced mRNA overexpression of inflammatory genes in Beas-2B cells.
Please insert Figure 6
In summary, through the optimization of R1 and R2, we designed and synthesized a series of Aza resveratrol-
chalcone compounds and evaluated their anti-inflammatory activities against LPS-induced IL-6 release in
mouse macrophages. The majority of analogs effectively inhibited LPS-induced production of IL-6. Among
them, five compounds, 5h, 6b, 6c, 6d and 6e exhibited excellent anti-inflammatory activity in a dose-
dependent manner along with low toxicity in vitro. The most promising compound 6b, was selected for as-
sessment of its anti-inflammatory activity in vivo, and the results indicated that 6b exhibited significant protec-
tion against LPS-induced acute lung injury in a mouse model. Although the animal model results for 6b did
not indicate as high a potential as the cell levels because of poor solubility and physical and chemical proper-
ties, this can be improved by converting 6b to its acid salt. In addition to the optimization of solubility, the in-
flammatory mechanism and underlying targets are still under investigation in our group. Overall, the potent
effects of these compounds on LPS-induced inflammation suggest that Aza resveratrol-chalcone compounds
are novel and promising compounds for further anti-inflammatory drug development and research, and com-
pound 6b could be a lead compound for the development of anti-ALI agents.
Acknowledgement
Financial support was provided by the National Natural Science Foundation of China (81402783, 21272179
and 21472142), Zhejiang Provincial Natural Science Foundation (LQ14H310003), National “863” project
(2011AA02A113).
Supplementary data
Supplementary data associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2015.xx.xxx.
6

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7

Figure Legends
Figure 1. Parallel structure design strategy of Aza resveratrol and Chalcone
Scheme 1. Synthesis of compounds 5a-5m
Scheme 2. Synthesis of compounds 6a-6i
Table 1. Chemical structures and yields of compounds 5a-5m
Table 2. Chemical structures and yields of compounds 6a-6i
Figure 2. Resveratrol and Aza resveratrol-chalcone compounds inhibited LPS-induced IL-6 (A) and TNF-α
(B) secretion in MPM. Macrophages were plated at a density of 5.0×105/plate at 37 oC and 5% CO2, overnight.
Cells were pre-treated with Aza resveratrol-chalcone compounds and resveratrol (10 mM) for 30 min, then
treated with LPS (0.5 mg/mL) for 24 h. TNF-α and IL-6 levels in the culture media were measured by ELISA
and were normalized by the total protein. The results were expressed as the percent of LPS group. Each bar
represents mean SEM of 3 independent experiments. Statistical significance relative to LPS group was indi-
cated, *p < 0.05, **p < 0.01.
Figure 3. The cytotoxic evaluation (A) in HL-7702 cells as well as five active compounds inhibited LPS-
induced IL-6 (B) release in a dose-dependent manner in MPM. Macrophages were plated at a density of
o
5.0×105/plate at 37 C and 5% CO2 overnight. Cells were pre-treated with Aza resveratrol-chalcone analogs
(5h, 6b, 6c, 6d, 6e) in a series concentration of 1 mM, 2.5 mM, 5 mM, 10 mM and resveratrol (10 mM) for 30
min, then treated with LPS (0.5 mM/mL) for 24 h. IL-6 levels in the culture media were measured by ELISA
and were normalized by the total protein. The results were expressed as the percent of LPS. Each bar repre-
sents mean SEM of 3 independent experiments. Statistical significance relative to LPS group was indicated,
*p < 0.05, **p < 0.01.
Figure 4. Resveratrol and 6b attenuate the LPS-induced ALI in mice. Mice were intratracheal instillation of
LPS. 6 hours later, mice were anaesthetized and killed. Bronchoalveolar lavage fluid and lung tissues were
collected for further tests. (A) Wet/Dry ratio. (B) Total amount of cells in BALF. (C) Protein concentration in
BALF. (D) HE stain.
Figure 5. Resveratrol and 6b attenuate the LPS-induced acute lung inflammation in mice. Mice were
intratracheal instillation of LPS. 6 hours later, rats were anaesthetized and killed. Bronchoalveolar lavage fluid
and lung tissues were collected for further tests. (A) The amount of TNF-α in serum. (B) The amount of TNF-
α in BALF. (C) Immunohistochemical of CD68 stain.
Figure 6. Mice was sacrificed and total RNA in lung was extracted. The mRNA levels of inflammatory cyto-
kines were detected by QPCR (A-D). The results were presented as the percent of LPS control. Each bar repre-
sents the mean SEM of the mice in group. Statistical significance relative to the LPS group was indicated,
*P<0.05; **P<0.01.
8

Figure 1

Figure 2
150
IL-6
100
50
0
*
*
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
i
5
LPS 0.5 g/mL
TNF-
200
150
100
50
*
**
**
**
*
**
**
**
**
0
g
LPS 0.5 g/mL

Figure 3
A
HL7702
100
50
0
*
**
IL-6
B
IC50=
2.8
1.8
4.8
3.6
3.6 µM
100
*
*
*
*
**
*
**
**
*
**
*
50
0
*
**
**
**
**
**
**
10
1
2.5 5
5h
1 2.5 5 10
6b
1 2.5 5 10
6c
1 2.5 5 10
6d
1 2.5 5 10
6e
LPS 0.5 µg/mL

Figure 4
B
A
1 5
C
1 0 0
4 0
3 0
2 0
1 0
0
8 0
6 0
4 0
2 0
0
1 0
**
*
*
**
5
0
S h am -
R e s -
L P S
6 b -
S h am -
L P S -
6 b -
S h am -
L P S -
R e s -
L P S
L P S -
R e s +
L P S
6 b +
V eh icle
L P S
V eh icle
V eh icle
V eh icle
L P S
V eh icle
V eh icle
L P S
D
6b-LPS
LPS
CON
RES-LPS

Figure 5
A
CD68
CON
C
LPS
6b-LPS
RES-LPS
B

Figure 6
B
A
100
150
IL-1β
IL-6
80
60
40
20
0
100
50
0
*
*
*
*
C
D

Scheme 1
O
O
O
a
b
MeO
MeO
MeO
NH2
NO2
1
2
3
c
O
R1
O
R1
MeO
d
N
MeO
OH
4a-4m
NH2
OMe
5a-5m
Reagents and conditions: (a) H2SO4/HNO3, 0 oC, 45 min, 90%; (b) 10% Pd/C,
H2, EtOH, 3 h, 96%; (c)R1CHO, 20%NaOH, EtOH, overnight, 40-85%; (d) 2-
hydroxy-3-methoxybenzaldehyde, Methanol, overnight, 30-90%
Scheme 2

Table 1
O
R1
MeO
N
OH
OMe
Comp.
R1
R1
Comp.
Yield (%)
46.5%
Yield (%)
30.0%
OMe
OMe
5a
5h
Br
OMe
F
36.3%
5b
5c
MeO
5i
5j
43.1%
78.0%
F
60.9%
40.1%
F3C
OMe
5d
OMe
Br
MeO
OAll
S
5k
5l
60.2%
50.0%
36.9%
5e
5f
77.0%
90.0%
30.2%
CF3
OMe
5m
Br
5g
OMe
9

Table 2
10

Design, synthesis and biological evaluation of paralleled Aza resveratrol-chalcone com-
pounds as potential anti-inflammatory agents for the treatment of acute lung injury
Wenbo Chen a, #, Xiangting Ge b, #, Fengli Xu b, Yali Zhang a, Zhiguo Liu a, Jialing Pan a, Jiao Song a, Yuanrong Dai b,
Jianmin Zhou c, *, Jianpeng Feng a, *, Guang Liang a
a Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University
Town, Wenzhou, Zhejiang 325035, China
b Department of respiration, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
c School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
Graphical abstract:
Paralleled Aza resveratrol-chalcone compounds were synthesized and evaluated for anti-
inflammatory activities in the treatment of ALI.
11